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DOI: 10.1002/ange.201002591

Chemie

Homogeneous Catalysis

Cooperative Catalytic Reactions Using Organocatalysts and TransitionMetal Catalysts: Enantioselective Propargylic Alkylation of Propargylic Alcohols with Aldehydes**
Masahiro Ikeda, Yoshihiro Miyake, and Yoshiaki Nishibayashi*
In the last decade, remarkable progress has been made toward the development of asymmetric reactions using organocatalysts under operationally simple and environmentally friendly reaction conditions.[1] Especially secondary amines derived from naturally available compounds worked as effective catalysts to promote asymmetric reactions of electrophiles with carbonyl compounds, such as aldol condensations and 1,4-conjugate additions, with high to excellent enantioselectivity.[2] In these reaction systems, enamines generated in situ from carbonyl compounds, such as aldehydes and ketones, and secondary amines worked as suitable carbon-centered nucleophiles. Nowadays, the methodology using organocatalysts realizes the diastereo- and enantioselective preparation of highly functionalized compounds such as ()-Oseltamivir.[3, 4] We have previously found that the ruthenium-catalyzed propargylic alkylation of propargylic alcohols with acetone as a carbon-centered nucleophile gives the corresponding products with a high enantioselectivity (up to 82 % ee).[5] Unfortunately, the use of an excess amount of simple ketones such as acetone was necessary to promote the propargylic alkylation. We have envisaged that the enamines generated in situ from aldehydes and secondary amines can be applied as carbon-centered nucleophiles for the asymmetric propargylic alkylation. As an extension of our study on enantioselective propargylic substitution reactions,[6] we have now found the ruthenium-catalyzed propargylic alkylation of propargylic alcohols with aldehydes in the presence of a catalytic amount of a secondary amine as an organocatalyst gives the corresponding products in high yields with an excellent enantioselectivity. In the present reaction system, both the transition-metal catalyst (ruthenium complex) and organocatalyst (secondary amine) activate the propargylic
[*] M. Ikeda, Dr. Y. Miyake, Prof. Dr. Y. Nishibayashi Institute of Engineering Innovation, School of Engineering The University of Tokyo Yayoi, Bunkyo-ku, Tokyo, 113-8656 (Japan) Fax: (+ 81) 3-5841-1175 E-mail: ynishiba@sogo.t.u-tokyo.ac.jp Homepage: http://park.itc.u-tokyo.ac.jp/nishiba/ [**] This work was supported by Grant-in-Aids for Scientific Research for Young Scientists (S) (No. 19675002) and for Scientific Research on Priority Areas (No. 18066003) from the Ministry of Education, Culture, Sports, Science and Technology (Japan). Y.N. thanks the Ube Industries LTD. M.I. acknowledges the Global COE program for Chemistry Innovation. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201002591.
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alcohol and aldehyde, respectively, thereby cooperatively promoting the enantioselective propargylic alkylation (Scheme 1). We believe that the method herein may provide a new type of dual catalytic reaction using both organocatalysts and transition-metal catalysts.[7, 8] Preliminary results are described herein.

Scheme 1. Cooperative catalytic reactions using organocatalysts and transition-metal catalysts.

Treatment of 1-phenyl-2-propyn-1-ol (1 a) with 3-phenylpropanal (2 a) in the presence of catalytic amounts of (S)-a,a,bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethyl silyl ether (3 a), methanethiolate-bridged diruthenium complex [{Cp*RuCl(m2-SMe)}2] (Cp* = h5-C5Me5 ; 4 a), and NH4BF4 in toluene at room temperature for 140 hours gave 2-benzyl-3-phenyl-4-pentynal (5 a) exclusively (Scheme 2). After the reduction of 5 a using NaBH4 at 0 8C for one hour, 2-benzyl-3-phenyl-4-pentyn-1-ol (6 a) was isolated in 87 % yield as a mixture of two diastereoisomers (syn6 a/anti-6 a = 2.2:1) with 94 % ee for syn-6 a and 88 % ee for anti-6 a. Only two equivalents of 2 a relative to 1 a were used as a carbon-centered nucleophile; this is in sharp contrast to the previous reaction system for propargylic alkylation, wherein a large amount (i.e., as solvent) of the simple ketone was necessary to promote the propargylic alkylation.[5] The reaction proceeded more smoothly when three equivalents of 2 a relative to 1 a were used under the same reaction conditions. Other secondary amines such as (5S)-2,2,3-tri-

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appended to the propargylic alcohol substantially increased the enantioselectivity (Table 1, entry 6). Similarly, a high enantioselectivity was observed when naphthyl-2-propyn-1-ols (1 g and 1 f) were used as substrates (Table 1, entries 7 and 8). No reaction occurred when 1cyclohexyl-2-propyn-1-ol (1 i) was used as a substrate under the same reaction conditions (Table 1, entry 9). These results indicate that the presence of an aryl moiety at the propargylic position of 1 is necessary to promote the catalytic reaction with a high enantioselectivity. Propargylic alkylation with other aldehydes also proceeded smoothly to give the corresponding products with a high enantioselectivity. Typical results are shown in Table 2. The reaction of 1 a with 3-(4-chloro)phenylpropanal Scheme 2. Enantioselective propargylic alkylation of propargylic alcohols with aldehydes. [a] 1,2-Dichloroethane was used as a solvent in place of toluene. Bn = benzyl, (2 b) under the same reaction conditions gave TMS = trimethylsilyl. the corresponding alkylated product with a similarly high enantioselectivity (Table 2, entry 1). When other aldehydes such as heptanal (2 c), 3-cyclohexylpropanal (2 d), and 6-chlorohexanal methyl-5-benzyl-4-imidazolidinone (3 b) worked effectively, (2 e) were used the corresponding products were obtained in but a substantially lower diastereo- and enantioselectivity high yields as a mixture of two diastereoisomers, each with were observed. Separately, we confirmed that the use of high enantioselectivity (Table 2, entries 24). Reactions of 1either 3 a or 4 a did not promote the propargylic alkylation. (2-methoxyphenyl)-2-propyn-1-ol (1 f) with aldehydes also This result indicates that both 3 a and 4 a cooperatively work gave a similar result (Table 2, entries 58). These results as catalysts to promote the catalytic reaction enantioselecindicate that a variety of aldehydes are available for the tively. propargylic alkylation. Next, alkylation of a variety of propargylic alcohols was To obtain some information on the enantioselective carried out by using 3 a and 4 a as co-catalysts. Typical results propargylic alkylation, the stereochemistry of the product are shown in Table 1. The introductuion of methyl, fluoro, syn-6 p was determined. The reaction of diastereochemically chloro, or methoxy group at the para position of the benzene pure syn-6 p with (1S)-10-camphorsulfonyl chloride and ring appended to the propargylic alcohols did not significantly triethylamine in the presence of a catalytic amount of 4affect the reactivity and enantioselectivity of the reaction dimethylaminopyridine (DMAP) was run at room temper(Table 1, entries 25). Interestingly, the introductuion of a ature for 18 hours to give syn-7 p in 87 % yield upon isolation methoxy group at the ortho position of the benzene ring (Scheme 3). After one recrystallization of syn-7 p, the enantio- and diastereomerically pure syn-7 p was isolated, and its Table 1: Enantioselective propargylic alkylation of propargylic alcohols 1 absolute configuration was determined as [(2R,3S)] by X-ray with the aldehyde 2 a.[a] analysis.[9] We investigated the stoichiometric and catalytic reactions to gain insight into the reaction pathway. Treatment of a rutheniumallenylidene complex 8 g[10] with three equivalents of 2 a and one equivalent of 3 a at room temperature for 45 hours and subsequent reduction with NaBH4 gave 6 g in syn-6/ Entry 1 t Yield ee [%][d] 49 % yield as a mixture of two diastereoisomers [syn-6 g/anti[h] of 6[b][%] anti-6[c] syn-6 anti-6 6 g = 3.0:1; syn-6 g (94 % ee), anti-6 g (86 % ee)] as shown in Scheme 4. Furthermore, the reaction of 1 g with 2 a in the 1 R = Ph (1 a) 90 89 (6 a) 2.2:1 96 89 presence of catalytic amounts of 8 g and 3 a at room temper50 90 (6 b) 2.5:1 97 86 2 R = p-MeC6H4 (1 b)
3 4 5 6 7 8 9 R = p-FC6H4 (1 c) R = p-ClC6H4 (1 d) R = p-MeOC6H4 (1 e) R = o-MeOC6H4 (1 f ) R = 1-naphthyl (1 g) R = 2-naphthyl (1 h) R = cyclohexyl (1 i) 120 120 120 40 90 120 90 88 (6 c) 85 (6 d) 85 (6 e) 93 (6 f ) 91 (6 g) 87 (6 h) 0 (6 i) 2.1:1 2.2:1 2.0:1 3.3:1 3.1:1 3.0:1 95 95 92 99 96 97 87 84 68 93 84 86

[a] Reaction conditions: 1 (0.20 mmol), 2 a (0.60 mmol), 3 a (0.01 mmol), 4 a (0.01 mmol), and NH4BF4 (0.02 mmol) were combined in toluene (6 mL) at room temperature. [b] Yield of isolated product. [c] Determined by 1H NMR analysis. [d] Determined by HPLC analysis.

Scheme 3. The stereochemistry of the propargylic alkylated product.

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Table 2: Enantioselective propargylic alkylation of propargylic alcohols 1 with the aldehydes 2.[a]

Chemie

Entry 1 2 3 4 5 6 7 8

1 R1 = Ph (1 a) R1 = Ph (1 a) R1 = Ph (1 a) R1 = Ph (1 a) R1 = o-MeOC6H4 R1 = o-MeOC6H4 R1 = o-MeOC6H4 R1 = o-MeOC6H4

2 R2 = p-ClC6H4CH2 (2 b) R2 = Me(CH2)4 (2 c) R2 = CyCH2 (2 d)[e] R2 = Cl(CH2)4 (2 e) R2 = p-ClC6H4CH2 (2 b) R2 = Me(CH2)4 (2 c) R2 = CyCH2 (2 d)[e] R2 = Cl(CH2)4 (2 e)

t [h] 90 90 90 120 40 40 70 60

Yield of 6[b] [%] 90 (6 j) 91 (6 k) 81 (6 l) 80 (6 m) 85 (6 n) 90 (6 o) 86 (6 p) 91 (6 q)

syn-6/ anti-6[c] 2.2:1 1.7:1 2.1:1 1.8:1 3.0:1 2.1:1 2.1:1 2.5:1

ee [%][d] syn-6 anti-6 96 92 96 88 97 97 98 98 87 85 78 89 95 52 92 90

(1 f ) (1 f ) (1 f ) (1 f )

[a] Reaction conditions: 1 (0.20 mmol), 2 (0.60 mmol), 3 a (0.01 mmol), 4 a (0.01 mmol), and NH4BF4 (0.02 mmol) were combined in toluene (6 mL) at room temperature. [b] Yield of isolated product. [c] Determined by 1H NMR analysis. [d] Determined by HPLC analysis. [e] 3-Cyclohexylpropanal. Cy = cyclohexyl.

mers (syn-5 and anti-5), we propose transition states between the rutheniumallenylidene complex and the enamine as shown in Scheme 7. The bulky substituents on the pyrrolidine ring efficiently shield the Re face of the favored anti-(E)enamine (Scheme 6).[12] For the formation of syn-5 (Scheme 7 a), the Si face of enamine attacks the Re face of allenylidene complex leading to the carboncarbon bond formation. In contrast, for the formation of anti-5 (Scheme 7 b), the Si face of enamine attacks the Si face of allenylidene complex for the carboncarbon bond formation. The predominant formation of syn5 is a result of the steric repulsion between the phenyl group at the gcarbon atom of the allenylidene

Scheme 4. The stoichiometric reaction of rutheniumallenylidene complex with an aldehyde in the presence of an amine.

ature for 90 hours and subsequent NaBH4 reduction afforded 6 g in 85 % yield as a mixture of two diastereoisomers [syn-6 g/ anti-6 g = 3.0:1; syn-6 g (97 % ee), anti-6 g (85 % ee)]. Independently, we confirmed that no reaction occurred when the reaction of the propargylic alcohol bearing an internal alkyne moiety was carried out under the same reaction conditions. These results clearly indicate that this propargylic alkylation proceeded with rutheniumallenylidene complexes serving as the key reactive intermediates.[11] A proposed reaction pathway is shown in Scheme 5. The initial step is the formation of the allenylidene complex B by the reaction of propargylic alcohol 1 with 4 a via the vinylidene complex A. Subsequent attack of the enamine E, generated in situ from aldehyde 2 and amine 3, upon the gcarbon atom of B results in the formation of the vinylidene complex D via the alkynyl complex C. Then, the alkylated product 5 is formed from D by ligand exchange with another propargylic alcohol 1. As described in our previous reports,[10] we believe that the synergistic effect between two ruthenium atoms in the diruthenium complexes is also quite important to promote this catalytic reaction. The E conformation of the enamine is energetically favored over its Z conformation, and the large aryl and silyl substituents at the a position of the pyrrolidine ring disfavored the syn form of enamine (Scheme 6).[12] To account for the highly enantioselective formation of both diastereoisoAngew. Chem. 2010, 122, 7447 7451

Scheme 5. Reaction pathway for the propargylic alkylation of propargylic alcohols with aldehydes.

Scheme 6. The conformation of enamines generated from amines and aldehydes.

ligand and the bulky substituents in the enamine. At present, we observed only the moderate diastereoselectivity of the alkylated products 5, but this is the first successful example of the enantioselective propargylation of aldehydes with propargylic alcohols to give the corresponding chiral b-ethynyl aldehydes.[13] www.angewandte.de

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C. Grondal, M. R. M. Httl, Angew. Chem. 2007, 119, 1590; Angew. Chem. Int. Ed. 2007, 46, 1570; c) A. Dondoni, A. Massi, Angew. Chem. 2008, 120, 4716; Angew. Chem. Int. Ed. 2008, 47, 4638; d) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli, Angew. Chem. 2008, 120, 6232; Angew. Chem. Int. Ed. 2008, 47, 6138; e) D. W. C. MacMillan, Nature 2008, 455, 304; f) S. Bertelsen, K. A. Jrgensen, Chem. Soc. Rev. 2009, 38, 2178; g) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167. D. Enders, M. R. M. Httl, C. Grondal, G. Raabe, Nature 2006, 441, 861. H. Ishikawa, T. Suzuki, Y. Hayashi, Angew. Chem. 2009, 121, 1330; Angew. Chem. Int. Ed. 2009, 48, 1304. Y. Inada, Y. Nishibayashi, S. Uemura, Angew. Chem. 2005, 117, 7893; Angew. Chem. Int. Ed. 2005, 44, 7715. a) H. Matsuzawa, Y. Miyake, Y. Nishibayashi, Angew. Chem. 2007, 119, 6608; Angew. Chem. Int. Ed. 2007, 46, 6488; b) K. Fukamizu, Y. Miyake, Y. Nishibayashi, J. Am. Chem. Soc. 2008, 130, 10498; c) G. Hattori, H. Matsuzawa, Y. Miyake, Y. Nishibayashi, Angew. Chem. 2008, 120, 3841; Angew. Chem. Int. Ed. 2008, 47, 3781. For recent reviews, see: a) Z. Shao, H. Zhang, Chem. Soc. Rev. 2009, 38, 2745; b) M. Klussmann, Angew. Chem. 2009, 121, 7260; Angew. Chem. Int. Ed. 2009, 48, 7124; c) P. de Armas, D. Tejedor, F. Garca-Tellado, Angew. Chem. 2010, 122, 1029; Angew. Chem. Int. Ed. 2010, 49, 1013. For recent examples, see: a) M. Rueping, A. P. Antonchick, C. Brinkmann, Angew. Chem. 2007, 119, 7027; Angew. Chem. Int. Ed. 2007, 46, 6903; b) S. Mukherjee, B. List, J. Am. Chem. Soc. 2007, 129, 11336; c) K. Sorimachi, M. Terada, J. Am. Chem. Soc. 2008, 130, 14452; d) M. Terada, Y. Toda, J. Am. Chem. Soc. 2009, 131, 6354; e) C. Li, B. Villa-Marcos, J. Xiao, J. Am. Chem. Soc. 2009, 131, 6967; f) Z.-Y. Han, H. Xiao, X.-H. Chen, L.-Z. Gong, J. Am. Chem. Soc. 2009, 131, 9182; g) Y. Lu, T. C. Johnstone, B. A. Arndtsen, J. Am. Chem. Soc. 2009, 131, 11284; h) S. Belot, K. A. Vogt, C. Besnard, N. Krause, A. Alexakis, Angew. Chem. 2009, 121, 9085; Angew. Chem. Int. Ed. 2009, 48, 8923; i) K. L. Jensen, P. T. Franke, C. Arrniz, S. Kobbelgaard, K. A. Jrgensen, Chem. Eur. J. 2010, 16, 1750. CCDC 765651 (syn-7 p) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. a) Y. Nishibayashi, M. D. Milton, Y. Inada, M. Yoshikawa, I. Wakiji, M. Hidai, S. Uemura, Chem. Eur. J. 2005, 11, 1433; b) S. C. Ammal, N. Yoshikai, Y. Inada, Y. Nishibayashi, E. Nakamura, J. Am. Chem. Soc. 2005, 127, 9428. For recent reviews of transition metal/allenylidene complexes, see: a) C. Bruneau, P. H. Dixneuf, Angew. Chem. 2006, 118, 2232; Angew. Chem. Int. Ed. 2006, 45, 2176; b) Metal Vinylidenes and Allenylidenes in Catalysis: From Reactivity to Applications in Synthesis (Eds.: C. Bruneau, P. H. Dixneuf), Wiley-VCH, Weinheim, 2008 ; c) V. Cadierno, J. Gimeno, Chem. Rev. 2009, 109, 3512. For recent examples, see: a) J. Franzn, M. Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjrsgaard, K. A. Jrgensen, J. Am. Chem. Soc. 2005, 127, 18 296; b) H. Jiang, A. Falcicchio, K. L. Jensen, M. W. Paixo, S. Bertelsen, K. A. Jrgensen, J. Am. Chem. Soc. 2009, 131, 7153. The produced chiral b-alkynyl aldehydes can be readily converted into the functionalized compounds without loss of enantioselective purity. For a recent example, see: T. Nishimura, T. Sawano, T. Hayashi, Angew. Chem. 2009, 121, 8201; Angew. Chem. Int. Ed. 2009, 48, 8057. For recent reviews, see: a) Y. Nishibayashi, S. Uemura, Curr. Org. Chem. 2006, 10, 135; b) Y. Nishibayashi, S. Uemura in Comprehensive Organometallic Chemistry III, Vol. 11 (Eds.: R. H. Crabtree, D. M. P. Mingos), Elsevier, Amsterdam, 2007,
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[3] [4] [5] [6]

[7]

Scheme 7. The high enantioselectivity of propargylic alkylated products. a) Path for the formation of the major diastereoisomer. b) Path for the formation of the minor diastereoisomer.

[8]

In summary, we have found the enantioselective propargylic alkylation of propargylic alcohols with aldehydes in the presence of a thiolate-bridged diruthenium complex and a secondary amine as the co-catalysts to give the corresponding propargylic alkylated products in excellent yields as a mixture of two diastereoisomers, each with high enantioselectivity (up to 99 % ee). This catalytic reaction is considered to be a new type of enantioselective propargylic substitution reaction,[14] wherein the enamines generated in situ from aldehydes enantioselectively attack the rutheniumallenylidene complexes. In the present reaction system, both the transitionmetal catalyst (ruthenium complex) and organocatalyst (secondary amine) activate propargylic alcohols and aldehydes, respectively, and cooperatively work to promote the enantioselective propargylic alkylation. We believe that the finding described herein will open a new aspect of not only dual catalytic reactions using both organocatalysts and transition-metal catalysts, but also the enantioselective aalkylation of aldehydes.[15, 16] Additional work is currently in progress to apply this strategy to other reaction systems.
Received: April 30, 2010 Published online: July 13, 2010

[9]

[10]

[11]

[12]

Keywords: alkynes homogeneous catalysis organocatalysis ruthenium synthetic methods

[13] [1] For recent reviews, see: a) Asymmetric Organocatalysis (Eds.: A. Berkessel, H. Grger), Wiley-VCH, Weinheim, 2005 ; b) Enantioselective Organocatalysis (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2007; c) Asymmetric Organocatalysis (Ed.: B. List), Springer, Heidelberg, 2010. [2] For recent reviews, see: a) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471; b) D. Enders,

[14]

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p. 123; c) G. W. Kabalka, M.-L. Yao, Curr. Org. Synth. 2008, 5, 28; d) N. Ljungdahl, N. Kann, Angew. Chem. 2009, 121, 652; Angew. Chem. Int. Ed. 2009, 48, 642; e) Y. Miyake, S. Uemura, Y. Nishibayashi, ChemCatChem 2009, 1, 342; f) R. J. Detz, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org. Chem. 2009, 6263. [15] For a recent review, see: A.-N. Alba, M. Viciano, R. Rios, ChemCatChem 2009, 1, 437. [16] For recent examples, see: a) D. A. Nicewicz, D. W. C. MacMillan, Science 2008, 322, 77; b) R. R. Shaikh, A. Mazzanti, M. Petrini, G. Bartoli, P. Melchiorre, Angew. Chem. 2008, 120, 8835; Angew. Chem. Int. Ed. 2008, 47, 8707; c) P. G. Cozzi, F. Benfatti, L. Zoli, Angew. Chem. 2009, 121, 1339; Angew. Chem. Int. Ed. 2009, 48, 1313.

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